Pentamidine

Mechanisms of Reduced Drug Uptake

Reduced drug uptake is a prominent mechanism of this compound resistance across various pathogens.

In African trypanosomes (Trypanosoma brucei), resistance to this compound is frequently linked to alterations in specific membrane transporters. The high-affinity this compound transport (HAPT1) activity is notably absent in this compound-adapted trypanosome lines. nih.gov While the P2 aminopurine transporter, encoded by the TbAT1 gene, was initially implicated in diamidine uptake and resistance, its loss results in only a modest decrease in this compound sensitivity and is not the primary cause of clinical treatment failure. mdpi.com More critically, the aquaglyceroporin 2 (TbAQP2) has been identified as a key determinant of this compound sensitivity and resistance. mdpi.com In resistant strains, the wild-type TbAQP2 gene may be absent or replaced by a chimeric protein formed through recombination with parts of the closely related TbAQP3 gene. The expression of a wild-type copy of TbAQP2 can fully reverse the resistance phenotype. In contrast, the low affinity this compound transport (LAPT1) activity often remains unchanged in these resistant lines. nih.gov These changes ultimately lead to a reduced accumulation of this compound inside the trypanosome cell. mdpi.com

In Leishmania species (Leishmania mexicana), this compound-resistant parasites exhibit a substantial decrease in drug accumulation. nih.govresearchgate.netasm.org Although the apparent affinity (Km) of the carrier for this compound is not altered, the apparent maximal velocity (Vmax) of uptake is reduced. nih.govresearchgate.netasm.org Furthermore, resistant Leishmania cells demonstrate an increased efflux of this compound, meaning a larger proportion of the accumulated drug is released compared to wild-type cells. nih.govresearchgate.netasm.org This resistance phenotype is also accompanied by a lack of mitochondrial accumulation of the drug and its exclusion from the parasite's mitochondrion, potentially linked to a reduced mitochondrial membrane potential observed in resistant cells. nih.govresearchgate.net

The table below illustrates the difference in intracellular this compound accumulation between wild-type and resistant Leishmania mexicana promastigotes:

In Acinetobacter baumannii , a bacterium, this compound resistance can be influenced by the AdeAB efflux system, which is regulated by the AdeRS two-component signal transduction system. plos.org Deletion of the adeRS genes has been shown to result in an 8-fold decrease in this compound resistance. plos.org The mechanism of this compound action in Gram-negative bacteria is thought to primarily involve binding to the lipid-A component of the outer membrane, rather than an intracellular target. plos.orgbiorxiv.org Additionally, growth conditions, such as the availability of different carbon sources or iron levels, can significantly alter the this compound resistance profile in A. baumannii. plos.orgbiorxiv.org

Alterations in Drug Target Sites

For this compound, resistance is predominantly associated with mechanisms that prevent the drug from reaching its intracellular targets, rather than direct alterations or mutations in the target sites themselves. mdpi.com In Trypanosoma parasites, this compound is known to bind to adenine-thymine-rich regions of DNA and inhibit mitochondrial topoisomerase enzymes. wikipedia.org However, the observed resistance largely stems from impaired drug uptake and accumulation, preventing sufficient concentrations of the drug from reaching these targets. mdpi.com Similarly, in Acinetobacter baumannii, this compound's primary interaction is believed to be with the outer membrane's lipid-A component, suggesting that resistance mechanisms in this context would likely involve changes to membrane integrity or efflux rather than modifications to an enzymatic target. plos.orgbiorxiv.org

Systemic Absorption Patterns

Pentamidine demonstrates varied absorption patterns depending on the route of administration. Following intravenous or intramuscular injection, the drug is well and completely absorbed. wikipedia.orgunboundmedicine.com In contrast, systemic absorption after inhalation is minimal. unboundmedicine.comnih.govpogo.ca Studies have shown that plasma concentrations after aerosol administration are significantly lower, approximately 5% to 10% of those achieved with equivalent parenteral doses. medsafe.govt.nznih.gov Specifically, one study noted that peak plasma levels in AIDS patients receiving aerosolized this compound were at or below the lower limit of detection (2.3 ng/mL). drugs.com Another study with AIDS patients reported average peak plasma levels of 18.8 ± 11.9 ng/mL after the first aerosol dose. drugs.com

Oral administration of this compound results in unreliable absorption. wikipedia.org

A comparison of pharmacokinetic parameters following a single 4 mg/kg dose in AIDS patients revealed significant differences between intramuscular and intravenous routes. hres.ca

Interactive Table: this compound Pharmacokinetic Parameters

Tissue and Organ Concentration Profiles

This compound is extensively distributed throughout the body and tends to bind to tissues and plasma proteins. wikipedia.orgunboundmedicine.com It concentrates in several organs, notably the liver, kidneys, lungs, spleen, pancreas, and adrenal glands. wikipedia.orgunboundmedicine.compfizer.commims.com Research in animal models provides more specific details on this distribution.

In mice that received a single intraperitoneal injection of this compound, the highest concentrations were found in the kidneys, followed by the liver. drugs.comfda.gov Studies in dogs given intravenous this compound showed the highest concentration in the liver, followed by the kidneys and lungs. drugs.com The concentration of this compound in these organs was approximately 70 to 1000 times that of the peak serum concentration. drugs.com After repeated daily doses in dogs, the organs exhibited a further 3 to 7-fold accumulation, while serum concentrations did not change. drugs.com

Autoradiographic studies in rats after intravenous administration also demonstrated high concentrations in the kidneys, spleen, and bone marrow. nih.gov Notably, this compound does not effectively cross the blood-brain barrier to reach curative levels in the cerebrospinal fluid. wikipedia.orgnih.gov

Inhaled this compound results in high concentrations in the bronchoalveolar lavage fluid and sediment of the lungs, with minimal systemic distribution. wikipedia.orgnih.govdrugs.com A study in rats found that intravenous administration led to 87.5-fold and 62.3-fold higher concentrations in the liver and kidney, respectively, compared to aerosol administration. drugs.com

Intracellular Distribution within Pathogens

The selective action of this compound against certain protozoan pathogens is largely due to its selective accumulation within the pathogen rather than the host cell. researchgate.netnih.gov The drug's uptake is mediated by specific transporters on the pathogen's cell surface. researchgate.netnih.govlstmed.ac.uk

In Trypanosoma brucei, the causative agent of African trypanosomiasis, this compound is taken up by several transporters, including the P2 aminopurine transporter, the high-affinity this compound transporter (HAPT1), and the low-affinity this compound transporter (LAPT1). researchgate.netmdpi.com Once inside the trypanosome, this compound can accumulate to millimolar concentrations and is known to associate with the kinetoplast and nuclear DNA. mdpi.com Fluorescent analogues of this compound have been observed to rapidly illuminate the kinetoplast. mdpi.com Some research suggests that this compound uptake in trypanosomes might occur via endocytosis, with the aquaglyceroporin TbAQP2 acting as a high-affinity receptor. plos.org

In Leishmania species, this compound is taken up by a high-affinity transporter, likely a proton symporter. researchgate.net Following uptake into the cytoplasm, it is further concentrated within the mitochondrion. researchgate.netnih.gov Resistance to this compound in Leishmania mexicana has been linked to the exclusion of the drug from the mitochondrion. nih.govasm.org The ABC transporter PRP1 has also been implicated in conferring this compound resistance in Leishmania amastigotes. nih.gov

Renal Excretion Mechanisms and Saturable Transport

The kidneys are the primary route of elimination for this compound, with the drug being excreted largely unchanged in the urine. unboundmedicine.commims.comdrugs.comfda.gov Studies in mice have shown that the ratio of urinary to fecal excretion is approximately 4:1. drugs.comfda.gov

Research using isolated perfused rat kidneys has revealed that the renal transport of this compound is a complex process involving a combination of glomerular filtration, active tubular secretion, and passive reabsorption. oup.comnih.gov Evidence for active secretion comes from studies where co-administration of tetraethylammonium, an organic cation, significantly reduced the renal clearance of this compound. oup.comnih.gov

The excretion of this compound demonstrates non-linear kinetics, suggestive of a saturable transport mechanism. oup.comnih.gov At higher doses, the tubular transport system can become saturated, leading to decreased urinary excretion and increased accumulation of the drug in the kidney. oup.comnih.gov This saturation of luminal transport is a key factor contributing to the nephrotoxic potential of this compound. oup.comnih.gov Furthermore, this compound itself can inhibit the reabsorption of sodium in the distal nephron by blocking apical sodium channels, which can lead to hyperkalemia. nih.gov Limited data suggests that this compound is not significantly removed by hemodialysis or peritoneal dialysis. hres.capfizer.com

Long Terminal Half-Life and Drug Persistence

This compound exhibits a biphasic decline in plasma concentrations following administration. hres.capfizer.com An initial rapid distribution phase is followed by a much slower terminal elimination phase. pfizer.com The terminal elimination half-life has been reported to range from approximately 6.4 to 12 days following intravenous administration. pfizer.comdrugs.com Intramuscular administration can result in a half-life of around 7 to 11 hours. wikipedia.orgmims.com This long terminal half-life is indicative of a deep peripheral compartment where the drug is stored and slowly released. drugs.com

The persistence of this compound in the body is notable. The drug can be detected in the urine for six to eight weeks after therapy has ceased. hres.caoup.com This prolonged presence is due to its accumulation and slow elimination from tissue reservoirs, such as the liver and kidneys. pfizer.comnih.gov Studies in patients with impaired renal function have not found a strong correlation between creatinine clearance and plasma clearance or elimination half-life, although the half-life may be prolonged in severe renal impairment. pfizer.comnih.gov

Following inhalation, the pulmonary half-life is also very long, with the drug being detectable in bronchoalveolar lavage fluid for over 10 to 14 days, and in some cases up to 115 days after treatment completion. medsafe.govt.nznih.govnih.gov

Modifications of Aromatic Rings and Linkers

Researchers have extensively investigated the impact of altering the aromatic rings and the central linker of the this compound scaffold. researchgate.netnih.gov Modifications to the aromatic rings, such as the introduction of substituents or their replacement with different aromatic systems, can influence the molecule's electronic properties and its interaction with biological targets. nih.gov

The nature and length of the linker connecting the two aromatic moieties are critical determinants of the molecule's conformation and flexibility, which in turn affect its binding affinity to DNA and other cellular components. irb.hrwhiterose.ac.ukelifesciences.org Studies have explored a variety of linkers, including alkanediamides and those containing heteroatoms like oxygen, nitrogen, and sulfur. researchgate.netnih.gov For instance, replacing the pentane chain with a 1,4-piperazinediyl or a 1,3-phenylenediamide moiety has yielded compounds with increased activity against Pneumocystis carinii and reduced toxicity compared to this compound. researchgate.net The introduction of amide or secondary amine groups into the linker was explored to enhance protein-ligand interactions by providing both hydrogen bond donors and acceptors. whiterose.ac.uk

A key finding is that the linker's length and composition are strong determinants of high-affinity binding. elifesciences.org For example, analogues with a linker of 5-7 methylene units displayed submicromolar binding affinities, while those with shorter (3-4) or longer (8) linkers had lower affinity. elifesciences.org The inclusion of heteroatoms in the aliphatic linker, particularly in the absence of methoxy groups on the benzene rings, has been associated with higher activity against P. carinii. researchgate.netnih.gov

Introduction of Heterocyclic Moieties

A significant strategy in the development of this compound analogues has been the incorporation of heterocyclic rings. sci-hub.se This approach aims to create more conformationally restricted molecules and to explore new interactions with biological targets. irb.hrsci-hub.se Furan, pyridine, and benzimidazole are among the heterocyclic systems that have been integrated into the this compound structure, either as part of the linker or as replacements for the phenyl rings. irb.hrasm.orgnih.gov

For example, replacing the central benzene ring with a furan or pyridine dicarboxamide has led to compounds with altered biological activity and selectivity. irb.hrsci-hub.se The introduction of a furandicarboxamide core was found to increase antiproliferative activity and selectivity against certain tumor cell lines. irb.hrsci-hub.se Similarly, the synthesis of benzimidazole-pentamidine hybrids has yielded compounds with potent activity against a range of protozoa, including Trichomonas vaginalis, Giardia lamblia, and Entamoeba histolytica. nih.gov

The type of heterocyclic moiety and its point of attachment can have a profound impact on the drug's properties. For instance, in a series of dicationic substituted bis-benzimidazoles, bridging the benzimidazoles with a 2,6-pyridine linker resulted in compounds where the imidazoline-substituted analogue showed good activity against Candida albicans and Cryptococcus neoformans, while the amidine-substituted version was inactive. asm.org

Prodrug Strategies and Improved Bioavailability

A major limitation of this compound is its poor oral bioavailability, largely due to the highly basic nature of the amidine groups, which are protonated at physiological pH. unc.edu To overcome this, various prodrug strategies have been developed. Prodrugs are inactive or less active precursors that are converted to the active drug in the body. This approach aims to improve absorption and distribution. unc.eduasm.org

One of the most explored strategies involves the use of amidoximes. unc.eduasm.org Aromatic diamidoximes are less basic than the corresponding diamidines and are hypothesized to be more readily absorbed orally. asm.org Once absorbed, they are metabolically reduced by enzymes, such as the mitochondrial Amidoxime Reducing Component (mARC), to the active amidine form. asm.orggoogle.com The diamidoxime of this compound has been shown to be an orally effective anti-Pneumocystis agent. asm.org Another successful example is the prodrug DB289 (pafuramidine), an O-methylamidoxime derivative of furamidine (DB75), which has undergone clinical trials for sleeping sickness. unc.eduasm.org

Other prodrug approaches include the development of O-acyl amidoximes, which are considered double prodrugs. unc.edu These are first hydrolyzed by esterases to the amidoxime, which is then reduced to the amidine. unc.edunih.gov The diacetyldiamidoximeester of this compound is an example of this strategy, demonstrating improved lipophilicity and oral bioavailability in animal studies. google.comnih.gov Coupling this compound diamidoxime to dicarboxylic acids has also yielded prodrugs with excellent solubility and good oral bioavailability. google.com

Comparative Efficacy against Various Pathogens

Novel this compound analogues have been tested against a wide array of pathogens to determine their spectrum of activity and comparative efficacy relative to the parent drug and other standard treatments. researchgate.netasm.orgacs.org These pathogens include protozoa such as Trypanosoma brucei rhodesiense (causing African sleeping sickness), Plasmodium falciparum (malaria), and Leishmania donovani (leishmaniasis), as well as fungi like Pneumocystis carinii and various Candida species. asm.orgacs.org

In one extensive study, 65 this compound analogues were evaluated. acs.org Several dications (compounds 32, 64, and 66) showed antitrypanosomal activity equal to or greater than the standard drug melarsoprol. acs.org Nine analogues were more active against P. falciparum than artemisinin, and eight compounds exhibited antileishmanial activity equal to or better than this compound itself. acs.org The diimidazoline 66 emerged as a particularly promising candidate with excellent in vitro activities and high selectivity against all three protozoa, coupled with significant in vivo efficacy in a mouse model of trypanosomiasis. acs.org

Analogues have also shown promise against bacterial pathogens. This compound has been found to sensitize Gram-negative bacteria to antibiotics they are typically resistant to, such as rifampicin and novobiocin. nih.gov This synergistic effect was also observed in vivo, where a combination of this compound and novobiocin successfully treated mice infected with Acinetobacter baumannii. nih.gov Furthermore, some analogues have demonstrated activity against multidrug-resistant Pseudomonas aeruginosa strains when used in combination with other antibiotics. mdpi.com

The table below summarizes the in vitro activity of selected this compound analogues against various pathogens.

Selectivity and Cytotoxicity to Mammalian Cells

A critical aspect of developing new drugs is ensuring they are selective for the pathogen and have low toxicity to the host's cells. nih.govacs.org Therefore, a crucial step in the evaluation of this compound analogues is to assess their cytotoxicity against mammalian cell lines. nih.govacs.org The goal is to identify compounds that are highly potent against the target pathogen while exhibiting minimal effects on human cells, thus having a high selectivity index. rsc.org

Many studies have reported the synthesis of this compound analogues with significantly lower cytotoxicity than the parent compound. researchgate.netnih.govnih.gov For example, a series of 20 analogues designed as potential anti-Pneumocystis agents showed little to no cytotoxicity in mammalian cell cultures, a stark contrast to the known toxicity of this compound. nih.gov While these compounds were slightly less potent than this compound against P. carinii, their reduced toxicity makes them promising candidates for further development. nih.gov

In another study, a newly synthesized this compound derivative, WLC-4059, showed significantly less cytotoxicity compared to this compound, particularly at higher concentrations. mdpi.com This improved safety profile, combined with its efficacy, highlights the potential of rational drug design to create safer therapeutic agents. The selectivity of novel compounds for P. falciparum over human embryonic kidney (HEK293) cells has also been demonstrated, with some analogues showing selectivity indices greater than 600. rsc.org This suggests that the mechanisms of drug uptake or action in the parasite are sufficiently different from those in human cells to allow for a therapeutic window. rsc.org

The table below presents data on the cytotoxicity of selected this compound analogues.

Optimization of Antiprotozoal and Antifungal Properties

Structure-activity relationship (SAR) studies have been instrumental in optimizing the antiprotozoal and antifungal properties of this compound analogues. Research has demonstrated that modifications to various parts of the this compound scaffold, including the central linker and the terminal aromatic rings, can significantly impact efficacy and selectivity against different pathogens.

A comprehensive study involving 65 this compound analogues revealed that certain structural alterations led to enhanced activity against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani. acs.org For instance, dications 32 , 64 , and 66 showed antitrypanosomal activity equal to or greater than the standard drug melarsoprol. acs.org Notably, nine analogues were more potent against P. falciparum than artemisinin, and eight compounds displayed superior or equivalent antileishmanial activity compared to this compound itself. acs.org The diimidazoline analogue 66 emerged as a particularly promising candidate, exhibiting excellent in vitro activities, high selectivity, and significant in vivo efficacy in a mouse model of trypanosomiasis. acs.org

Further modifications, such as the introduction of a 2-pyridyl group in place of a phenyl ring, have also been explored. One study found that the 2-pyridyl analogue of this compound was more potent than the parent drug against both T. b. rhodesiense and P. falciparum. acs.org The development of mono-N-arylated this compound analogues has yielded compounds with sub-micromolar activity against kinetoplastid parasites, including strains resistant to this compound and diminazene. researchgate.net These analogues were also effective against Leishmania mexicana. researchgate.net

In the realm of antifungal research, twenty this compound analogues and thirty dicationic substituted bis-benzimidazoles were screened for their activity against Candida albicans and Cryptococcus neoformans. nih.gov A significant number of these compounds demonstrated potent inhibitory and fungicidal activity, with some exhibiting minimum inhibitory concentrations (MICs) comparable to amphotericin B and fluconazole. nih.gov Importantly, many of these analogues were also active against fluconazole-resistant strains and other fungal pathogens like Aspergillus fumigatus and Fusarium solani. nih.gov The presence of an arylalkyl substituent on the amidine function, however, was found to diminish antifungal activity against Pneumocystis carinii. mdpi.com

Table 1: Antiprotozoal and Antifungal Activity of Selected this compound Analogues This table is interactive. Users can sort columns by clicking on the headers.

Evaluation for Repurposed Applications (e.g., Antibacterial, Anti-cancer)

The potential of this compound and its analogues extends beyond their traditional use, with significant research focused on repurposing these compounds for antibacterial and anti-cancer therapies.

Antibacterial Applications:

This compound has been identified as a promising agent to combat multidrug-resistant (MDR) Gram-negative bacteria, not as a standalone antibiotic, but as an adjuvant that sensitizes these pathogens to existing antibiotics. nih.govamegroups.org It effectively perturbs the Gram-negative outer membrane by interacting with lipopolysaccharide (LPS), thereby increasing the permeability to other drugs. nih.govmdpi.com This synergistic effect has been demonstrated with antibiotics typically effective only against Gram-positive bacteria, such as rifampicin, novobiocin, and erythromycin. nih.govresearchgate.net

Studies have shown that this compound in combination with rifampicin is effective against a wide range of Gram-negative pathogens in vitro, and systemic Acinetobacter baumannii infections in mice. nih.gov This combination therapy has also shown promise against MDR Pseudomonas aeruginosa strains. mdpi.com Furthermore, this compound's adjuvant activity persists in polymyxin-resistant bacteria. nih.gov The development of this compound analogues has led to the synthesis of compounds with significant enhancement of the activity of Gram-positive specific antibiotics against E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa. researchgate.net

Anti-cancer Applications:

This compound has been proposed for repurposing in cancer therapy due to its ability to modulate various signaling pathways implicated in cancer progression. scienceopen.comnih.gov It has been shown to inhibit cancer cell proliferation, invasion, migration, and angiogenesis while inducing apoptosis and anti-tumor immune responses. scienceopen.comnih.gov These effects are mediated through the modulation of pathways such as PI3K/AKT, MAPK/ERK, and p53. scienceopen.comnih.govresearchgate.net

Recent studies have identified this compound as a small-molecule antagonist of the programmed death-ligand 1 (PD-L1). frontiersin.orgnih.govresearchgate.netnih.gov By binding to PD-L1, this compound can block the PD-1/PD-L1 interaction, thereby restoring T-cell activity and enhancing T-cell-mediated anti-cancer cytotoxicity. frontiersin.orgnih.govresearchgate.netnih.gov In vivo studies using a PD-L1 humanized syngeneic mouse tumor model demonstrated that this compound attenuated tumor growth and prolonged survival. frontiersin.orgnih.gov Histological analysis revealed an increased number of tumor-infiltrating lymphocytes in this compound-treated mice. frontiersin.orgnih.govresearchgate.net

Furthermore, amino analogues of this compound have demonstrated antiproliferative activity in the MCF-7 human breast cancer cell line. ptfarm.pl this compound has also been shown to inhibit the S100B-p53 interaction in glioma cells, leading to apoptosis. spandidos-publications.com

Table 2: Repurposed Applications of this compound and its Analogues This table is interactive. Users can sort columns by clicking on the headers.

Molecular Electrostatic Potential (MEP) Analysis

Molecular Electrostatic Potential (MEP) analysis is a computational technique used to visualize the charge distribution of a molecule and predict how it will interact with other molecules. rsdjournal.org This method has been applied to study this compound and its derivatives to identify key structural features necessary for their biological activity, particularly against Trypanosoma brucei rhodesiense. rsdjournal.orgrsdjournal.org

MEP studies help in understanding the reactive sites of the molecules and their potential interactions with biological receptors. rsdjournal.org For this compound analogues, MEP analysis has been used to guide the design of new compounds with potentially enhanced activity. rsdjournal.org The distribution of negative and neutral MEP values on the surface of molecular cavities has been shown to influence the binding of cationic drugs like this compound. rsc.org The Breneman model is often used to compute the ESP-atomic partial charges on the atoms, which are then used to reproduce the molecular electrostatic potential. rsc.orgnih.gov

Pattern Recognition Models

Pattern recognition models, such as Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA), and Soft Independent Modeling of Class Analogy (SIMCA), are statistical methods used to classify compounds based on their structural and physicochemical properties. rsdjournal.orgscielo.brresearchgate.netscielo.br These models have been successfully employed to study a series of this compound derivatives with activity against T. b. rhodesiense. rsdjournal.org

By reducing the dimensionality of a data matrix containing various molecular descriptors, these models can classify compounds into different activity classes (e.g., more active or less active). rsdjournal.org A study on twenty-eight this compound derivatives identified that properties like the highest occupied molecular orbital (HOMO) energy, molecular volume (VOL), and the water-accessible surface area of all polar atoms (ASA_P) are crucial for constructing these classification models. rsdjournal.org The application of these models led to the identification of nine promising new compounds for synthesis and further biological evaluation. rsdjournal.org The 3D-WHIM descriptors, which capture information about the molecule's size, shape, and atom distribution, have also been used in PCA and SIMCA analyses to classify bisamidine conformations. scielo.brresearchgate.netscielo.br

Molecular Modeling and Docking Studies

Molecular modeling and docking are powerful computational techniques used to predict the binding orientation and affinity of a ligand to its target receptor. These methods have been extensively used to understand the interactions of this compound and its analogues with their biological targets, primarily the minor groove of B-DNA. ptfarm.plscielo.brnih.govnih.govbibliotekanauki.pl

Docking studies have shown that this compound analogues bind to the minor groove of DNA, with a preference for AT-rich sequences. ptfarm.pl The binding is stabilized by van der Waals and electrostatic interactions, which are considered more critical than specific hydrogen bonds. nih.gov The positive charge of the amidine groups facilitates interactions with the negatively charged phosphate backbone of DNA. ptfarm.pl

These studies have provided rationalizations for the differences in DNA-binding behavior observed among this compound analogues with varying linker chain lengths and aromatic ring substitutions. nih.gov For instance, furan-containing analogues have been shown to penetrate the minor groove more effectively and cause less structural perturbation upon binding compared to this compound. nih.gov Molecular dynamics (MD) simulations have also been used to study the stability of complexes between this compound derivatives and proteins like α1-acid glycoprotein (AGP), indicating that stable complexes are formed. nih.gov Docking studies have also been employed to investigate the interaction of this compound analogues with other targets, including the NMDA receptor and the hERG K+ channel. rsc.orgmeduniwien.ac.at

Hydration Protocols

Adequate hydration is a critical strategy to mitigate certain adverse effects associated with pentamidine administration, particularly nephrotoxicity and hypotension. Patients who are dehydrated may exhibit increased susceptibility to the nephrotoxic and hypotensive effects of parenteral this compound drugs.com. Therefore, correcting dehydration prior to initiating therapy is preferable drugs.com.

Research indicates that maintaining proper fluid balance can reduce the incidence and severity of side effects, including liver or kidney dysfunction, hypertension, hypotension, hypoglycemia, and hypokalemia drugbank.com. In clinical practice, additional intravenous fluids during this compound administration have been employed as a therapeutic intervention for managing adverse events plos.org. This approach aims to support renal function and blood pressure stability, thereby potentially reducing the risk of drug accumulation in the kidneys and subsequent toxicity drugs.comoup.comwikipedia.orgccjm.org.

Table 1: Impact of Hydration on this compound-Associated Adverse Effects

Dosage Adjustment Considerations

This compound exhibits complex pharmacokinetics, characterized by a long elimination half-life and significant tissue accumulation, even in individuals with normal renal function wikipedia.orgnih.govnih.gov. This accumulation can lead to increased trough concentrations with multiple dosing nih.govoup.com.

Research into dosage adjustments, particularly in the context of renal impairment, has yielded important findings. Studies have shown that renal clearance accounts for a small fraction (approximately 2.1% to 6%) of this compound's total plasma clearance pfizer.comnih.govhres.ca. Consequently, some research suggests that dosage adjustments may not be strictly necessary for patients with creatinine clearances greater than 35 mL/min nih.govoup.com. However, there is limited information on the kinetics or the full adverse effects profile of this compound in patients with severely impaired renal function (creatinine clearance <35 mL/min) pfizer.com.

Despite the low renal clearance, the drug's long half-life (ranging from 29 to 118 hours in some studies, and up to 12 days after the last dose in others) and accumulation potential suggest that lower dose regimens, while still efficacious, might be associated with reduced toxicity, especially with multiple dosing wikipedia.orgnih.govnih.govoup.com. The risk of nephrotoxicity may be higher in patients with AIDS, sometimes accompanied by severe hyperkalemia drugs.com. Therefore, careful monitoring of renal function (serum creatinine and blood urea nitrogen) and serum potassium levels is crucial, and a reduction in dosing frequency or withdrawal of therapy may be warranted if toxicity develops drugs.comnih.gov.

Table 2: Pharmacokinetic Parameters and Renal Function in this compound Administration

Co-administration with Modulating Agents

The co-administration of this compound with other agents can significantly influence its toxicity profile, primarily through pharmacokinetic and pharmacodynamic interactions. Research highlights several key areas of concern:

Nephrotoxic Agents: Concurrent or sequential use of this compound with other nephrotoxic drugs, such as aminoglycosides, amphotericin B, cisplatin, foscarnet, and vancomycin, should be closely monitored or avoided if possible, as their nephrotoxic effects may be additive drugbank.comdrugs.comdrugs.comnih.govresearchgate.net. This compound's renal transport involves filtration, secretion, and passive reabsorption, and inhibition of luminal transport by other medications can increase drug accumulation in the kidney, predisposing patients to toxicity oup.com.

QTc Prolonging Agents: this compound is known to prolong the QTc interval, increasing the risk of Torsade de Pointes and other serious arrhythmias drugbank.comdrugs.commedscape.commdpi.com. Co-administration with other drugs that also prolong the QTc interval (e.g., certain antiarrhythmics, antihistamines, antipsychotics, antidepressants, antibiotics like quinolones and macrolides, and antifungals) is often contraindicated or requires careful monitoring drugbank.comnih.govmedscape.com.

Agents Affecting Glucose Metabolism: this compound can cause both hypoglycemia and hyperglycemia due to its direct cytotoxic effects on pancreatic beta cells, leading to initial insulin release and subsequent insufficient insulin secretion drugs.comdrugs.comnih.govjwatch.orgamegroups.orghres.cabmj.com. Therefore, co-administration with drugs that can also affect blood glucose levels (e.g., diuretics, insulin, oral hypoglycemic agents) requires vigilant monitoring drugbank.comdrugs.compogo.camedscape.com.

Dideoxyinosine (ddI): In animal studies, co-administration of dideoxyinosine has been shown to increase the renal clearance of this compound, suggesting a potential interaction that could alter this compound disposition oup.com. However, the clinical implications of this interaction for toxicity mitigation require further characterization.

Table 3: Drug Interaction Categories and Mechanisms with this compound

Interactions Affecting Clearance of Other Drugs

Enhanced Efficiency and Targeted Delivery

Nanoparticles offer a promising platform for the targeted and efficient delivery of this compound. By encapsulating this compound within nanocarriers, it is possible to modify its pharmacokinetic profile and direct it to specific cells or tissues.

One approach involves the use of lipid-polymer hybrid nanoparticles. For instance, nanoparticles composed of poly(lactic-co-glycolic) acid (PLGA) and a hyaluronic acid (HA)-phospholipid conjugate have been developed. These particles, with a size below 150 nm and a high encapsulation efficiency of 90%, are designed to target cells that overexpress the CD44 receptor, a receptor for HA. unimi.itnih.gov This targeted delivery was demonstrated in vitro, where the HA-coated nanoparticles showed preferential and receptor-mediated cytotoxicity towards cancer cells with high CD44 expression. unimi.itnih.gov The presence of HA on the nanoparticle surface was shown to be crucial for this targeted effect, as confirmed by competition assays. unimi.it

Another strategy utilizes chitosan nanoparticles, which are biodegradable and biocompatible. This compound-loaded chitosan nanoparticles (PTN-CNPs) have been synthesized with a spherical shape and a size of 88 nm. msptm.org These nanoparticles demonstrated enhanced antileishmanial activity in vitro compared to free this compound, suggesting they act as a targeted drug delivery system. msptm.org The half-maximal inhibitory concentration (IC50) values of PTN-CNPs against Leishmania tropica promastigotes and amastigotes were significantly lower than those of the free drug. msptm.org

Furthermore, polymethacrylate nanoparticles have been explored for delivering this compound. These nanoparticles are taken up by macrophagic cells and localize within phagolysosomes, which can then fuse with parasitophorous vacuoles containing Leishmania parasites. nih.gov This intracellular trafficking allows for the targeted delivery of this compound to the site of infection. nih.gov

The table below summarizes the characteristics of different nanoparticle-based this compound delivery systems.

Release Kinetics and Intracellular Action

The release of this compound from nanoparticles is often pH-dependent, a feature that can be exploited for controlled drug release within specific cellular compartments. For example, this compound is bound to polymethacrylate nanoparticles through ionic interactions between the carboxylic acid groups of the polymer and the amine groups of the drug. nih.gov This interaction is sensitive to pH, with a decrease in pH leading to drug release. At a pH of 5, which is characteristic of lysosomes and parasitophorous vacuoles, up to 50% of the encapsulated this compound can be released. nih.gov

Similarly, the release of this compound from chitosan nanoparticles is sustained over time. In vitro studies have shown an initial rapid release of about 50% of the drug within the first 9 hours at pH 7.4, followed by a more gradual release, reaching approximately 92% after 36 hours. msptm.org Polycaprolactone (PCL) nanoparticles and liposomes have also been studied, releasing 12.13% and 22.21% of their this compound load, respectively, after 24 hours. tandfonline.com

Once inside the target cells, the nanoparticle-delivered this compound can exert its therapeutic effect. Ultrastructural studies have visualized the trafficking of drug-loaded polymethacrylate nanoparticles within Leishmania-infected Küpffer cells. nih.gov The nanoparticles are taken up by these phagocytic cells and are found within phagosomes that fuse with lysosomes. nih.gov These secondary lysosomes, containing the nanoparticles, then fuse with the parasitophorous vacuoles where the Leishmania amastigotes reside. nih.gov Although the nanoparticles were observed in close proximity to the parasites, direct internalization by the amastigotes was not seen. nih.gov This suggests that the released this compound is the active agent acting on the parasites within the vacuole. nih.gov

The enhanced efficacy of nanoparticle-encapsulated this compound is attributed to the higher intracellular drug concentration achieved compared to the administration of the free drug. unimi.it This increased intracellular delivery can overcome potential drug resistance mechanisms and lead to improved therapeutic outcomes. nih.gov

Localized Delivery and Systemic Absorption

When administered via inhalation, this compound accumulates on the bronchoalveolar surface at concentrations significantly higher than those achieved with parenteral administration. nih.gov In one study involving AIDS patients, the mean concentration of this compound in bronchoalveolar lavage fluid 18 to 24 hours after a single 300 mg inhaled dose was 23.2 ng/mL. drugs.com

Systemic absorption of aerosolized this compound is minimal. nih.govnih.gov The mean plasma concentration immediately following inhalation has been reported to be 13.84 ng/mL, which is only 5% of the mean peak plasma concentration observed after intravenous administration. nih.govasm.org Furthermore, repeated inhalation does not lead to drug accumulation in the plasma, a phenomenon that is observed with multiple intravenous doses. nih.govasm.org Cumulative urinary excretion of this compound 24 hours after the first inhaled dose is also only 5% of that seen with intravenous administration. nih.govasm.org

The table below provides a comparison of this compound concentrations after different routes of administration.

Pulmonary Pharmacokinetics

The pharmacokinetics of this compound in the lungs following aerosolized delivery are characterized by a long half-life. nih.gov Studies have shown that this compound can be detected in bronchoalveolar fluid for extended periods, with one patient having detectable levels 115 days after completing a two-week course of therapy. nih.govasm.org While this compound concentrations in the bronchoalveolar fluid were generally higher after two weeks of therapy compared to the first day, the difference was not statistically significant. nih.govasm.org

The deposition of aerosolized this compound in the lungs is influenced by the nebulizer system used. atsjournals.org The particle size generated by the nebulizer is a critical factor, with an ideal mass median aerodynamic diameter (MMAD) of 1 to 2 microns for optimal distribution throughout the lungs. nih.gov Jet nebulizers, such as the Respirgard II, produce particles within this ideal range. nih.gov The amount of drug deposited in the lungs has been found to be a major determinant of the resulting drug levels in pulmonary secretions. atsjournals.org